Protein May Hold Key to Metabolic Syndrome

Action Points

Inactivation of a protein (Ecscr also known as ARIA) that regulates endothelial cell signaling enhanced insulin sensitivity in mice and could represent a new therapeutic strategy for treating metabolic syndrome and possibly obesity.

Note that Ecscr represents a previously undescribed mode of regulation in energy metabolism and glucose homeostasis.

Inactivation of a protein that regulates endothelial cell signaling enhanced insulin sensitivity in mice and could represent a new therapeutic strategy for treating metabolic syndrome and possibly obesity, researchers reported.

The protein Ecscr (also known as ARIA) was highly expressed in white and brown adipose tissue and was found to regulate energy metabolism and glucose homeostasis by modulating endothelial cell function, researcher Yoshiki Akakabe of Kyoto Prefectural University of Medicine, in Kyoto, Japan, and colleagues wrote online in the journal Nature Communications.

In mouse studies, genetic deletion of Ecscr resulted in improved glucose tolerance and enhanced insulin sensitivity even in the absence of changes in body weight and body fat mass.

The researchers noted that Ecscr represents a previously undescribed mode of regulation in energy metabolism and glucose homeostasis.

"Until recently, there have been only a few reports of genetically modified mice that show enhanced insulin sensitivity under normal diet and concomitant resistance to diet-induced obesity," the researchers wrote. "The striking difference of Ecscr-deleted (Ecscr-/-) mice from these mice is that the enhanced insulin sensitivity under normal diet arises in the absence of leanness in Ecscr-/- mice. This unique metabolic phenotype of Ecscr-/- mice is due to the roles of Ecscr in both endothelial insulin signaling and adipose tissue angiogenesis."

The study involved Ecscr-/- and wild type (WT) mice, which served as controls. The mice were fed either a normal chow diet (containing 23.1% protein and 5.1% fat) or a high fat diet (containing 35% fat, 25.3% carbohydrate and 23% protein) beginning at the age of 6 weeks.

A pair-feeding study included Ecscr-/- mice allowed to feed at liberty from the age of 6 weeks and WT mice of the same age who ate the same volume of food.

Body weight, visceral or subcutaneous fat weight, as well as food intake, were similar between the Ecscr-/- and WT mice and no significant difference in body weight was seen in the pair-feeding studies.

Skeletal muscle blood flow is a major regulator of systemic insulin sensitivity, and insulin signaling and insulin-mediated Akt/endothelial nitric oxide synthase (eNOS) activation in endothelial cells has been shown to have a critical role in skeletal muscle insulin sensitivity by regulating muscle blood flow and insulin delivery into the skeletal muscle.

When they investigated the role of Ecscr in the progression of obesity, they found that deletion of the protein appeared to protect mice on the high-fat diets from obesity and obesity-related metabolic disorders.

"When challenged with a high-fat diet, weight gain was significantly attenuated in Ecscr-/- mice despite the indistinguishable food intake from WT mice," the researchers wrote. "This reduced weight gain in Ecscr-/- mice fed high-fat diets was also observed even under a pair-fed condition."

Hepatic steatosis was also ameliorated in the Ecscr-/- mice relative to WT mice on the high-fat diets, and leptin expression and serum cholesterol levels were lower (P<0.01).

Ecscr deletion was also found to enhance thermogenesis and metabolic rate in the presence of a high-fat diet and Ecscr activation in endothelial cells predisposed the mice to obesity.

Brown adipose tissue (BAT) is a thermogenic organ that has been shown to be critical in energy balance.

In a series of experiments, the researchers showed that thermogenesis and fatty acid uptake were considerably increased in the BAT of Ecscr-/- mice fed high-fat diets, and vascularization and hypoxia were significantly attenuated in the BAT of Ecscr-/- mice relative to WT mice following exposure to high-fat diets.

"Recent studies with PET computed tomography scanning using 18fluorodeoxyglucose have shown the presence of metabolically active BAT that contributes to energy expenditure in adult humans," the researchers concluded.

"Therefore, the inhibition of Ecscr potentially improves insulin sensitivity and concurrently counteracts obesity in humans as well, and thus Ecscr represents an attractive target for the control of metabolic disorders, although its role in other PTEN-controlled biological processes remains to be elucidated."

The research was supported, in part, by a grant from Takeda Science Foundation.

The researchers declare no competing financial interests.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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